Hypoxia Inducible Factor-1 Upregulates Adiponectin in Diabetic Mouse Hearts And Attenuates Post-Ischemic Injury

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Adiponectin is a circulating cytokine with important cardioprotective effects. Plasma adiponectin levels are significantly reduced in patients with insulin resistance and type II diabetes mellitus and cardiovascular disease. Although adiponectin is primarily synthesized by adipocytes, new studies reveal that adiponectin is secreted by other cell types, including cardiomyocytes. Control of adiponectin gene expression in heart and microvasculature is poorly understood. We investigated the regulation of adiponectin expression by the transcription factor hypoxia inducible factor-1 (HIF-1) and its role in attenuating cardiac reperfusion injury. HIF-1 regulation of adiponectin was examined by isolating and characterizing the murine adiponectin promoter. HIF-1-dependent activation of the murine adiponectin promoter was verified via electrophoretic mobility shift assays, transient transfection assays, and QPCR. We show for the first time that HIF-1 activation via an siRNA-mediated prolyl 4-hydroxylase-2 gene silencing strategy induced adiponectin mRNA expression in murine microvascular endothelium in vitro (17-fold), intact hearts (22-fold, wild type; 5-fold, obese/diabetic) and white adipose tissue (37-fold, wild-type; 9.6-fold, obese/diabetic). HIF-1-induced adiponectin expression was associated with improved myocardial viability in obese/diabetic mice (32% increase) and preservation of left ventricular function (36% increase in rate pressure product). Our studies suggest that local production of adiponectin by cardiomyocytes/microvascular endothelial cells may regulate cardiac function and indicate a novel strategy for protecting diabetic hearts from ischemia/reperfusion injury.